Trimethyl-pseudo-uric acid and process of preparing same.



UNITED STATES PATENT ()EFIQE.

EMIL FISCHER, OF BERLIN, GERMANY, ASSIGNOR TO 0. F. BOEHRINGER & SOEHNE,OF WALDHOF, GERMANY.

TRlMETHYL-PSEUDO-URIC ACID AND PROCESS 0F PREPARING SAME.

SPECIFICATION formingpart of Letters Patent No. 667,388, dated February5, i901. Application filed December 28, 1897. serial No. 664,083- (Nospecimens.)-

To all whom, it Wtay concern.-

Be it known that I, EMIL FISCHER, a citizen of the Empire of Germany,residing at Berlin, in the Empire of Germany,- have invented certain newand useful Improvements in Preparing Uric Acids and Their Derivatives;and I do hereby declare the following to be a full, clear, and exactdescription of the invention, such as Will enable others skilled in theart to which it ap pertains to make and use the same.

This invention relates to the preparation of uric acid and itsderivatives, and in particular the manufacture of the same from thecorresponding pseudo-uric acids.

Hitherto pseudo-uric acid could only be converted into uric acid byfusing or melting it together with oxalic acid. In operating withdimet-hyl-pseudo-uric acid in which the two methyl groups are bound tothe two nitrogen atoms of the alloxan nucleus the same result was alsoobtained by boiling with the anhydrid of acetic acid and zinc chlorid,as set forth in the article by E. Fischer and L. Ach in Berichte derDeatschen-Ohemr'schen Gesellschaft, Vol. 28, page 2473. Both processesare impracticable for industrial purposes and are only scientificallyvaluable. I have found that these conversions may be efiected in apractically available manner if the pseudouric acids are acted on in thewet way, preferably in the presence of mineral acids, although in somecases the mere heating of an aqueous solution is suflicient.

In order to make my invention, which consists in the methods, steps, andfeatures pointed out in the claims hereunto annexed, fully and clearlyunderstood by those skilled in the art, I will now describe a number ofexamples embodying the same. The proportions are all given by Weight.

1. Conversion of pseudo-aria acid into aria acid.To one part offinely-powdered pseudouric acid I add five hundred parts of hydrochloricacid of tWenty-per-cent. strength and boil the mixture until completesolution takes place, which occurs after some time. The liquid is thenevaporated over an open fire until it is reduced to about theone-fifteenth part of its original volume. As a result of this treatmentthe largest portion of the uric acid which has been formed is separatedout or precipitated in crystalline form. This separation takes placealready while the liquid is still warm. The liquid is then allowed tocool and diluted with Water (about ten parts) and then filtered. If purestarting material is employed in this process, the uric acid obtained iscompletely colorless and the yield represents over eighty per cent. ofthe pseudouric acid employed.

2. Preparation of gamma-dimethyZ-aric acid.I take one part of thedimethyl-pseudouric acid, which has been described by Techow in Berichteder Deatschen- C'herm'schen Gesellschaft, V01. 27, page 3088, and add toit seven parts of hydrochloric acid of twenty-percent. strength and heaton the water-bath. A clear solution forms in the beginning of theaction, and after about fifteen minutes the resultantgamma-dimethyl-uric acid crystallizes out of the solution. After thusheating for an hour the mass is allowed to cool and the crystals areseparated by filtration. In this process the yield also represents abouteighty per cent. of the pseudo-compound employed.

Instead of a twenty-per-cent. hydrochloric acid a one-per-cent. acid maybe employed; but in this case it is necessary to boil for from eight toten hours.

3. Preparation ofgammamonomethyZ-aric acid-By a reaction the same asthat employed for the production of pseudo-uric acid (see Liebig andWohler in Annalen, Vol. 26, page 266, and Baeyer, Ibt'd, Vol. 127, page3) I may obtain monomethyl-pseudo-uric acid having the formula HN-OO Ioo O.HN.OO.NH2

HNOO

if in the place of the sulfite of ammonium there employed a solution ofsulfite of methylamin is taken. The resultant gamma methylpseudo-uricacid dissolves in about twentythree parts of boiling water, and oncooling the solution it is thrown out in the form of very smallcolorless crystals containing one molecule of water of crystallization.The conversion into the corresponding uric acid takes place more rapidlythan in the two abovedescribed examples. If this monomethylpseudo-uricacid is heated to boiling with twenty times its quantity of hydrochloricacid of twelve-per-cent. strength a clear solution is first formed, andthe crystallization of the resultant gamma-monomethyl-uric acid beginsalready after the lapse of a few minutes and while the liquid is warm.After having heated the mass for about half an hour the reaction isclosed. The same is then allowed to cool, when the balance of themethyl-uric acid is thrown out to the largest extent in the form ofcrystals. In this case also the reaction proceeds almost quantitatively,and the resultant product is in every respect identical with thegamma-monomethyl-uric acid which has first been obtained by me fromtheobromin. (See Bem'chtc, Vol. 28, page 2492.)

The reaction takes place according to the equation If instead of thetwelve-per-cent. hydrochloric acid a one-per-cent. acid is employed, thereaction takes place in the same way, but requires a correspondinglylonger heating. The crystallization of the gamma monomethyl-uric acidthen begins after the lapse of about a half-hour, and after one andone-half hours the amount of the resultant uric acid will have alreadyreached two-thirds of the pseudo-uric acid employed. In this example thecooperation of the mineral acid is not even necessary, since the samereaction takes place when heating a mere aqueous solution of themethyl-pseudo-uric acid to 100 centigrade. Only under these conditionsit is m uch slower.

If, e. g., an approximately-saturated aqueous solution ofmonomethyl-pseudo-uric acid is heated on the water-bath, the separationof the gamma-monomethyluric acid commences after the lapse ofthree-quarters of an hour;

. but even at the end of three hours the con l o orLucoNH OI-I .N O0

and which is a new compound, first discovered es /Less by me, may beobtained from di methyl-alloxan according to known reactions byemploying sulfite of methylamin instead of the sulfite of ammonium. (SeeE. Fischer, Berichte der Deutschen- O hemischc'n Gesellsc hrtfi, Vol.30, page 564.) This method of preparation in detail is as follows: Whenacting on dimethyl-alloxan with neutral sulfite of methylamin, there isformed first a product of addition corresponding to the compounds of theketones with bisulfites. The same is constant in the cold and may beobtained in a crystalline form in the following manner: Five grams ofcommercial solution of methyl amin containing about thirty-three percent. of the base are saturated with sulfur dioxid, and then about fivegrams more of methylamin are added until the odor of the base becomesperceptible. Thereuponthe same is neutralized with carbonic-acid gas,whereupon asolutiou of five grams dimethyl-alloxan in five grams wateris added. It the liquid remains at the ordinary temperature, colorlessneedles are soon separated out in copious quantity, which are thenrecrystallized from a small quantity of warm water. If, however, theabove mixture of dimethyl-alloxan and methylamin sulfite, together withthe separated crystals, is allowed to stand at ordinary temperatu re,the crystals will go into solution after the lapse of about twenty-fourhours, and the solution now evidently contains the salt of a thio acid,since on heating with dilute hydrochloric acid abundant quantities ofsulfuric acid are formed. On heating the solution to from to centigradeand maintaining this temperature for one hour this thio salt is rapidlyformed, this reaction being attended by a further reaction which leadsto the formation of 1-3-7-trin1ethyluramil, which on cooling thesolution is separated from the same in crystalline form. Thistrimethyluramil,which has the structural formula:

GH .N-CO

co cnntuon cn,..N co

and which forms the intermediate product in my method of preparing theabove trimethylpseudo-uric acid, is a very stable body when dry andremains unchanged even in contact with air for a considerable time atordinary temperatures. When in a moist condition or in aqueous solution,the access of air soon colorsitpurple-red. Whenheatedtoover100centigrade in the capillary tube, it also turns red, and when rapidlyheated to 200 centigrade it is entirely decomposed without anysharply-defined melting action. In hot water it is soluble withcomparative facility, crystallizing out of the same in the form ofcolorless needles. It is still more soluble in dilute hydrochloric acid.It is also soluble in alkalies, but may be separated therefrom by immediately neutralizing with acetic acid. It is destroyed on boiling withalkalies.

The 1-3-7-triinethyl-uric acid is very readily prepared from thetrimethyluramil by heating the latter with a solution of cyanate ofpotassium. The crude product may be directly employed for this purposeif the same has been freed from ammonium salts by careful washing withcold water. For example, three grams of the 1-3-7-trimethyluramil areheated on the water-bath with two grams pure potassium dissolved in fivecubic centimeters of water. A clear solution soon forms and afterheating for half an hour the conversion will have been completed. Ifafter cooling the resulting colorless liquid is treated carefully withhydrochloric acid, the 1-3-7-trimethyl-uric acid will be precipitated inthe form of a crystalline powder. The trimethylpseudo-uric acid soobtained is soluble in about four parts hot Water and on coolingcrystallizes therefrom in the form of colorless obliqely-truncatedprisms of considerable size which contain one molecule of water ofcrystallization. This acid has no constant melting-point. On heating thesame rapidly it will melt with attendant decomposition in theneighborhood of 195 centigrade. When slowly heated, a partial meltingtakes place between 180 and 190 centigrade, a product of decompositionbeing then formed which does not melt at 300 centigrade. In alcohol itis only soluble with difficulty even when heated. In forminghydrochloric acid (specific gravity 1.19) it is readily soluble atordinary temperature. This trimethylpseudo-uric acid is, as I havefound, readily converted into the corresponding trimethyluric acid orhydroxycaffein. For this purpose one part of the trimethyl-pseudo-uricacid is heated, together with ten parts of hydrochloric acid ofone-per-cent. strength, on the water-bath. A clear solution first forms,and after the lapse of about a half-hour the trimethyl-uric acid beginsto separate out. At the end of one and one-half hours the mass isallowed to cool, and the crystalline precipitate which has formed isseparated by filtration. The reaction proceeds almost quantitatively.The trimethyl-uric acid is identical with hydroxycaffein, which,according to my recent researches, does not possess the molecularstructure formerly attributed to it, but must have the formula:

0H,.N-OO

I I Cl-I oo O-N oo I ll oH,.N-o-NH since by methylating in the wet wayit is readily converted into tetramethyl-uric acid.

cH,.N-co

I o on.N.oo.NH,-

Just as in the previous example, the reaction will take place also inthe absence of mineral acids; but in that case a much longer time isrequired for its completion. If, for example, a ten-per-cent. aqueoussolution of the trimethyl-pseudo-uric acid is heated to 100 centigrade,the crystallization of hydroxycafiein does not begin until after thelapse of several hours, and even after five hours the conversion will bescarcely half completed.

In the hereinbefore-described processes the hydrochloric acid may bereplaced by su1 furic acid and other mineral acids, and it is to beobserved, therefore, that my invention, generically considered, is notconfined to the particular mineral acid employed.

The term pseudo-uric acid as employed in the claims is to be understoodas covering both the pseudo-uric acid proper as well as its alkylderivationsthe alkyl-pseudo-uric acids.

What I claim, and desire to secure by Letters Patent, is-

1. The process of preparing trimethylpseudo-uric acid which consists intreating dimethyl-alloxan with sulfite of methylamin.

2. As a new chemical compound, trimethylpseudo-uric acid having theformula above given and which dissolves in about four parts of hotwater, and crystallizes therefrom in colorless, obliquely-truncatedprisms which contain one molecule of water of crystallization.

3. The process of preparing a uric acid which consists in heating apseudo-uric-acid solution.

4. The process of preparing a uric acid which consists in heating apseudo-uric acid in the presence of a mineral acid.

5. The process of preparing a uric acid which consists in addinghydrochloric-acid solution to a pseudo-uric acid and heating themixture.

6. The process of preparing trimethyl-uric acid or hydroxycafi'ein whichconsists in heating trimethyl-pseudo-uric acid in solution.

7. The process of preparing trimethyl-uric acid which consists inheating trimethylpseudo-uric acid in the presence of a mineral acid.

8. The process of preparing trimethyl-uric acid which consists in addinghydrochloric acid to trimethyl-pseudo-uric acid and heating the mixture.

9. The process of preparing trimethyl-uric acid which consists in addingone part of tri-

